Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C

Niewold, Timothy B.; Swedler, William I.

doi:10.1007/s10067-004-1024-2

Cited by 162 publications

(112 citation statements)

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“…IFN-a-based treatments are widely used for viral hepatitis and carcinoid tumors; however, several case reports have emerged describing autoimmune conditions that have developed during IFN-a therapy. [13][14][15] These observations in human and murine lupus implicate a complicated role of the type I IFN involved in lupus pathogenesis. We hypothesize that inappropriate activation of type I interferon (IFN) signaling pathways, combined with a genetic predisposition, may be important in SLE pathogenesis.…”

Section: Introductionmentioning

confidence: 93%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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Interferon (IFN)-a is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/ W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lprand normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-a treatment. Analysis of IFN-a-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-a including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/ lpr and/or BALB/c mice. Of IFN-a-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-a treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-a response in two lupus-prone models, and help to have an insight into the role of IFN-a in lupus pathogenesis Genes and Immunity (2007) IntroductionSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a break of immune tolerance to self antigens, resulting in inflammation and damage to a range of organ systems. The exact pathoetiology of SLE remains elusive. Elevated serum levels of IFN-a have long been observed and correlated with disease activity. A series of studies using microarray gene expression analysis in patient peripheral blood cells demonstrated an 'IFN signature' in SLE, which correlated with renal and hematological involvement of phenotypes. [1][2][3][4][5][6] Supporting evidence has also come from studies on murine lupus. The (New Zealand Black (NZB) Â New Zealand White (NZW))F1 hybrid female mice (NZB/W) develop a disease closely resembling human SLE, characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous IFN-a/b R-deleted NZB mice had significantly reduced antierythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. 7 In contrast to normal BALB/c mice, continuous in vivo treatment of IFN-a in pre-autoimmune NZB/W mice from 8 weeks of age precipitates the autoimmune process and kidney damage, leading to premature death from severe immune complex glomerulonephritis. This result provides a direct evidence that IFN-a is implicated in the pathogenesis of SLE. 8 Thus, the type I IFNs have emerged as a dominant target in the path...

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Section: Introductionmentioning

confidence: 93%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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“…2,3 Additionally, a number of patients treated with recombinant human IFN-a for malignancy and chronic viral hepatitis have developed de novo SLE, which typically resolves after the IFN-a is discontinued. 4,5 Our group and others have shown that SLE patients exhibit coordinate overexpression of IFN-ainduced genes in their peripheral blood mononuclear cells (PBMCs) as compared with healthy individuals and patients with other inflammatory diseases such as rheumatoid arthritis. [6][7][8] Increased IFN-a-induced gene expression correlates with greater disease activity and particular autoantibody profiles and disease phenotypes in SLE patients.…”

Section: Introductionmentioning

confidence: 99%

High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus

et al. 2007

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Interferon a (IFN-a) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-a activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-a activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-a activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-a activity, concordance in affected sib pairs and frequent transmission of the high IFN-a activity trait from parents to offspring. Autoantibodies to RNAbinding proteins and double-stranded DNA were associated with high IFN-a activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-a activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-a activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.

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“…Evidence of the effect of INF-in SLE comes from observations on the therapeutic administration of IFN-in various types of malignancies and hepatitis C infection. Case reports emerged describing the development of lupus associated autoantibodies and even clinical lupus (Niewold & Swedler 2005). Discontinuation of IFN-α typically resulted in remission of SLE symptoms, supporting a causal relationship with IFN-α.…”

Section: Interferon-αmentioning

confidence: 96%